Use of pyridinyl-pyrimidinylamino-benzamide derivatives for the treatment of amyloid related disorders

ABSTRACT

The invention relates to the use of an inhibitor of formula I  
                 
or a N-Oxide or a pharmaceutically acceptable salt thereof having an activity on protein kinases VEGFR-2, Tie-2, c-Src, c-Met, FGFR-1, Flt-1, HER-2, c-Abl, c-Raf, PDGFR-beta, c-Kit, or on a combination of the above enzymes, for the treatment and/or prevention of neurological and vascular disorders related to beta-amyloid generation and/or aggregation such as neurodegenerative diseases like Alzheimer&#39;s disease, Down&#39;s Syndrome, memory and cognitive impairment, dementia, amyloid neuropathies, brain inflammation, nerve and brain trauma, vascular amyloidosis, or cerebral hemorrhage with amyloidosis

The invention relates to the use of compounds (hereinafter: “COMPOUND”)or a N-Oxide or a pharmaceutically acceptable salt thereof having anactivity on protein kinases VEGFR-2, Tie-2, c-Src, c-Met, FGFR-1, Flt-1,HER-2, c-Abl, c-Raf, PDGFR-beta, c-Kit, or on a combination of the aboveenzymes, for the treatment and/or prevention of neurological andvascular disorders related to beta-amyloid generation and/or aggregationsuch as neurodegenerative diseases like Alzheimer's disease, Down'sSyndrome, memory and cognitive impairment, dementia, amyloidneuropathies, brain inflammation, nerve and brain trauma, vascularamyloidosis, or cerebral hemorrhage with amyloidosis.

COMPOUND is preferably a compound of formula I

wherein

R₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl,acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-loweralkyl, or phenyl-lower alkyl;

R₂ represents hydrogen, lower alkyl, optionally substituted by one ormore identical or different radicals R₃, cycloalkyl, benzcycloalkyl,heterocyclyl, an aryl group, or a mono- or bicyclic heteroaryl groupcomprising zero, one, two or three ring nitrogen atoms and zero or oneoxygen atom and zero or one sulfur atom, which groups in each case areunsubstituted or mono- or polysubstituted;

and R₃ represents hydroxy, lower alkoxy, acyloxy, carboxy, loweralkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl,amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an arylgroup, or a mono- or bicyclic heteroaryl group comprising zero, one, twoor three ring nitrogen atoms and zero or one oxygen atom and zero or onesulfur atom, which groups in each case are unsubstituted or mono- orpolysubstituted;

or wherein R₁ and R₂ together represent alkylene with four, five or sixcarbon atoms optionally mono- or disubstituted by lower alkyl,cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy, amino, mono- ordisubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl;benzalkylene with four or five carbon atoms; oxaalkylene with one oxygenand three or four carbon atoms; or azaalkylene with one nitrogen andthree or four carbon atoms wherein nitrogen is unsubstituted orsubstituted by lower alkyl, phenyl-lower alkyl, loweralkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl,N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, loweralkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl,pyrimidinyl, or pyrazinyl;

R₄ represents hydrogen, lower alkyl, or halogen;

Or more preferably COMPOUND is a compound selected from

-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzanilide,-   4-Methyl-N-(3-pyridinyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   N-(4-Chlorophenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   2(R)- and    2(S)-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoylamino]propanoic    acid,-   4-Methyl-3-[[4-(3-pyrdinyl)-2-pyrmidinyl]amino]-N-(8-quinolinyl)benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-[trifuoromethoxy]phenyl)benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(2-pyrrolidinoethyl)benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-pyrrolidinophenyl)benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(1-[2-pyrimidinyl]-4-piperidinyl)benzamide,-   N-(4-Di-[2-methoxyethyl]amino-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   N-(4-[1H-Imidazolyl]-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(2-pyrrolidino-5-trifluoromethylphenyl)benzamide,-   N-(3,4-difluorophenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifluoromethylbenzyl)benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifluoromethylphenyl)benzamide,-   N-(3-Chloro-5-trifluoromethylphenyl)4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   N-(4-Dimethylaminobutyl)4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-N-[4-(4-methyl-1-piperazinyl)-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2,2,2-trifluoroethoxy)-3-trifluoromethylphenyl]benzamide,-   4-Methyl-N-[4-(2-methyl-1H-imidazolyl)-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-N-(4-phenyl-3-trifluoromethylphenyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-N-[4-(4-methyl-1H-imidazolyl)-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   Methyl 2(R) and    2(S)-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoylamio]-3-]4-hydroxyphenyl]propanoate,-   N-[2-(N-Cyclohexyl-N-methylaminomethyl)phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   N-[3-[2-(1H-Imidazolyl)ethoxy]phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-N-[3-morpholino-5-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridnyl)-2-pyrimidinyl]amino]-N-(4-pyrrolidino-3-trifluoromethylphenyl)benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(4-piperidino-3-trifluoromethylphenyl)benzamide,-   4-Methyl-N-[4-morpholino-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   N-(4-Ethylamino-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifluoromethoxyphenyl)benzamide,-   N-[4-(2-Hydroxypropylamino)-3-trifluoromethylphenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   N-(4-Diethylamino-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(3-pyridinyl)-5-trifluorophenyl]benzamide,-   N-[3-[3-(1H-Imidazolyl)propoxy]phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(3-pyridinyl)-3-trifluorophenyl]benzamide,-   4-Methyl-N-[3-(4-methyl-1-piperazinyl)-5-trifluorophenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-N-[3-methylcarbamoyl-5-trifluorophenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,-   4-Methyl-N-[3-methylcarbamoyl-5-morpholino]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide.-   Further compounds which are even more particularly preferred are:-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[3-(1H-imidazol-1-yl)propoxy]-phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[2-(1H-imidazol-1-yl)ethoxy]phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(ethylamino)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(diethylamino)-3-(trifluoromethyl)phenyl]benzamide,-   (±)-4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-[(2-hydroxypropyl)amino]-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-[bis(2-methoxyethyl)amino]-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1-piperidinyl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-morpholinyl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-phenyl-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[4-(3-pyridinyl)-3-(trifluoromethyl)phenyl]methyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)2-pyrimidinyl]amino]-N-[4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2,4-dimethyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2-methyl-1H-imidazol-1-yl)3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-morpholinyl)-5-[(methylamino)carbonyl]phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[(methylamino)carbonyl]-5-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(3-pyddinyl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-morpholinyl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(5-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl]benzamide,    and-   4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl]benzamide.

or most preferably COMPOUND is4-Methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidehaving the formula I

Compounds of formula I and methods for the preparation of such compoundsare in particular generically and specifically disclosed in the patentsand patent application PCT/EP03/07198, in particular in the compoundclaims and the final products of the working examples, thesubject-matter of the final products, the pharmaceutical preparationsand the claims is hereby incorporated into the present application byreference to this publication.

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated:

The prefix “lower” denotes a radical having up to and including amaximum of 7, especially up to and including a maximum of 4 carbonatoms, the radicals in question being either linear or branched withsingle or multiple branching.

Where the plural form is used for compounds, salts, and the like, thisis taken to mean also a single compound, salt, or the like.

Any asymmetric carbon atoms may be present in the (R)-, (S)- or(R,S)-configuration, preferably in the (R)- or (S)-configuration. Thecompounds may thus be present as mixtures

of isomers or as pure isomers, preferably as enantiomer-purediastereomers.

The invention relates also to possible tautomers of the compounds offormula I.

Lower alkyl is preferably alkyl with from and including 1 up to andincluding 7, preferably from and including 1 to and including 4, and islinear or branched; preferably, lower alkyl is butyl, such as n-butyl,sec-butyl, isobutyl, tert-butyl, propyl, such as n-propyl or isopropyl,ethyl or methyl. Preferably lower alkyl is methyl, propyl or tert-butyl.

Lower acyl is preferably formyl or lower alkylcarbonyl, in particularacetyl.

An aryl group is an aromatic radical which is bound to the molecule viaa bond located at an aromatic ring carbon atom of the radical. In apreferred embodiment, aryl is an aromatic radical having 6 to 14 carbonatoms, especially phenyl, naphthyl, tetrahydronaphthyl, fluorenyl orphenanthrenyl, and is unsubstituted or substituted by one or more,preferably up to three, especially one or two substituents, especiallyselected from amino, mono- or disubstituted amino, halogen, lower alkyl,substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl, hydroxy,etherified or esterified hydroxy, nitro, cyano, carboxy, esterifiedcarboxy, alkanoyl, benzoyl, carbamoyl, N-mono- or N,N-disubstitutedcarbamoyl, amidino, guanidino, ureido, mercapto, sulfo, lower alkylthio,phenylthio, phenyl-lower alkylthio, lower alkylphenylthio, loweralkylsulfinyl, phenylsulfinyl, phenyl-lower alkylsulfinyl, loweralkylphenylsulfinyl, lower alkylsulfonyl, phenylsulfonyl, phenyl-loweralkylsulfonyl, lower alkylphenylsulfonyl, halogen-lower alkylmercapto,halogen-lower alkylsulfonyl, such as especiallytrifluoromethanesulfonyl, dihydroxybora (—B(OH)₂), heterocyclyl, a mono-or bicyclic heteroaryl group and lower alkylene dioxy bound at adjacentC-atoms of the ring, such as methylene dioxy. Aryl is more preferablyphenyl, naphthyl or tetrahydronaphthyl, which in each case is eitherunsubstituted or independently substituted by one or two substituentsselected from the group comprising halogen, especially fluorine,chlorine, or bromine; hydroxy; hydroxy etherified by lower alkyl, e.g.by methyl, by halogen-lower alkyl, e.g. trifluoromethyl, or by phenyl;lower alkylene dioxy bound to two adjacent C-atoms, e.g. methylenedioxy,lower alkyl, e.g. methyl or propyl; halogen-lower alkyl, e.g.trifluoromethyl; hydroxy-lower alkyl, e.g. hydroxymethyl or2-hydroxy-2-propyl; lower alkoxy-lower alkyl; e.g. methoxymethyl or2-methoxyethyl; lower alkoxycarbonyl-lower alkyl, e.g.methoxy-carbonylmethyl; lower alkynyl, such as 1-propynyl; esterifiedcarboxy, especially lower alkoxycarbonyl, e.g. methoxycarbonyl,n-propoxy carbonyl or iso-propoxy carbonyl; N-mono-substitutedcarbamoyl, in particular carbamoyl monosubstituted by lower alkyl, e.g.methyl, n-propyl or iso-propyl; amino; lower alkylamino, e.g.methylamino; di-lower alkylamino, e.g. dimethylamino or diethylamino;lower alkylene-amino, e.g. pyrrolidino or piperidino; loweroxaalkylene-amino, e.g. morpholino, lower azaalkylene-amino, e.g.piperazino, acylamino, e.g. acetylamino or benzoylamino; loweralkylsulfonyl, e.g. methylsulfonyl; sulfamoyl; or phenylsulfonyl.

A cycloalkyl group is preferably cyclopropyl, cyclopentyl, cyclohexyl orcycloheptyl, and may be unsubstituted or substituted by one or more,especially one or two, substitutents selected from the group definedabove as substitutents for aryl, most preferably by lower alkyl, such asmethyl, lower alkoxy, such as methoxy or ethoxy, or hydroxy, and furtherby oxo or fused to a benzo ring, such as in benzcyclopentyl orbenzcyclohexyl.

Substituted alkyl is alkyl as last defined, especially lower alkyl,preferably methyl; where one or more, especially up to three,substituents may be present, primarily from the group selected fromhalogen, especially fluorine, amino, N-lower alkylamino, N,N-di-loweralkylamino, N-lower alkanoylamino, hydroxy, cyano, carboxy, loweralkoxycarbonyl, and phenyl-lower alkoxycarbonyl. Trifluoromethyl isespecially preferred.

Mono- or disubstituted amino is especially amino substituted by one ortwo radicals selected independently of one another from lower alkyl,such as methyl; hydroxy-lower alkyl, such as 2-hydroxyethyl; loweralkoxy lower alkyl, such as methoxy ethyl; phenyl-lower alkyl, such asbenzyl or 2-phenylethyl; lower alkanoyl, such as acetyl; benzoyl;substituted benzoyl, wherein the phenyl radical is especiallysubstituted by one or more, preferably one or two, substituents selectedfrom nitro, amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino,hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, andcarbamoyl; and phenyl-lower alkoxycarbonyl, wherein the phenyl radicalis unsubstituted or especially substituted by one or more, preferablyone or two, substituents selected from nitro, amino, halogen, N-loweralkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, loweralkoxycarbonyl, lower alkanoyl, and carbamoyl; and is preferably N-loweralkylamino, such as N-methylamino, hydroxy-lower alkylamino, such as2-hydroxyethylamino or 2-hydroxypropyl, lower alkoxy lower alkyl, suchas methoxy ethyl, phenyl-lower alkylamino, such as benzylamino,N,N-di-lower alkylamino, N-phenyl-lower alkyl-N-lower alkylamino,N,N-di-lower alkylphenylamino, lower alkanoylamino, such as acetylamino,or a substituent selected from the group comprising benzoylamino andphenyl-lower alkoxycarbonylamino, wherein the phenyl radical in eachcase is unsubstituted or especially substituted by nitro or amino, oralso by halogen, amino, N-lower alkylamino, N,N-di-lower alkylamino,hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl, carbamoylor aminocarbonylamino. Disubstituted amino is also lower alkylene-amino,e.g. pyrrolidino, 2-oxopyrrolidino or piperidino; loweroxaalkylene-amino, e.g. morpholino, or lower azaalkylene-amino, e.g.piperazino or N-substituted piperazino, such as N-methylpiperazino orN-methoxycarbonylpiperazino.

Halogen is especially fluorine, chlorine, bromine, or iodine, especiallyfluorine, chlorine, or bromine.

Etherified hydroxy is especially C₈-C₂₀ alkyloxy, such as n-decyloxy,lower alkoxy (preferred), such as methoxy, ethoxy, isopropyloxy, ortert-butyloxy, phenyl-lower alkoxy, such as benzyloxy, phenyloxy,halogen-lower alkoxy, such as trifluoromethoxy, 2,2,2-trifluoroethoxy or1,1,2,2-tetrafluoroethoxy, or lower alkoxy which is substituted by mono-or bicyclic hetero-aryl comprising one or two nitrogen atoms, preferablylower alkoxy which is substituted by imidazolyl, such as1H-imidazol-1-yl, pyrrolyl, benzimidazolyl, such as 1-benzimidazolyl,pyridyl, especially 2-, 3- or 4-pyridyl, pyrimidinyl, especially2-pyrimidinyl, pyrazinyl, isoquinolinyl, especially 3-isoquinolinyl,quinolinyl, indolyl or thiazolyl.

Esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, loweralkoxycarbonyloxy, such as tert-butoxycarbonyloxy, or phenyl-loweralkoxycarbonyloxy, such as benzyloxycarbonyloxy.

Esterified carboxy is especially lower alkoxycarbonyl, such astert-butoxycarbonyl, iso-propoxycarbonyl, methoxycarbonyl orethoxycarbonyl, phenyl-lower alkoxycarbonyl, or phenyloxycarbonyl.

Alkanoyl is primarily alkylcarbonyl, especially lower alkanoyl, e.g.acetyl.

N-Mono- or N,N-disubstituted carbamoyl is especially substituted by oneor two substituents independently selected from lower alkyl,phenyl-lower alkyl and hydroxy-lower alkyl, or lower alkylene, oxa-loweralkylene or aza-lower alkylene optionally substituted at the terminalnitrogen atom.

A mono- or bicyclic heteroaryl group comprising zero, one, two or threering nitrogen atoms and zero or one oxygen atom and zero or one sulfuratom, which groups in each case are unsubstituted or mono- orpolysubstituted, refers to a heterocyclic moiety that is unsaturated inthe ring binding the heteroaryl radical to the rest of the molecule informula I and is preferably a ring, where in the binding ring, butoptionally also in any annealed ring, at least one carbon atom isreplaced by a heteroatom selected from the group consisting of nitrogen,oxygen and sulfur; where the binding ring preferably has 5 to 12, morepreferably 5 or 6 ring atoms; and which may be unsubstituted orsubstituted by one or more, especially one or two, substitutentsselected from the group defined above as substitutents for aryl, mostpreferably by lower alkyl, such as methyl, lower alkoxy, such as methoxyor ethoxy, or hydroxy. Preferably the mono- or bicyclic heteroaryl groupis selected from 2H-pyrrolyl, pyrrolyl, imidazolyl, benzimidazolyl,pyrazolyl, indazolyl, purinyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl,naphthyridinyl, quinoxalyl, quinazolinyl, quinnolinyl, pteridinyl,indolizinyl, 3H-indolyl, indolyl, isoindolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, triazolyl, tetrazolyl, furazanyl,benzo[d]pyrazolyl, thienyl and furanyl. More preferably the mono- orbicyclic heteroaryl group is selected from the group consisting ofpyrrolyl, imidazolyl, such as 1H-imidazol-1-yl, benzimidazolyl, such as1-benzimidazolyl, indazolyl, especially 5-indazolyl, pyridyl, especially2-, 3- or 4-pyridyl, pyrimidinyl, especially 2-pyrimidinyl, pyrazinyl,isoquinolinyl, especially 3-isoquinolinyl, quinolinyl, especially 4- or8-quinolinyl, indolyl, especially 3-indolyl, thiazolyl,benzo[d]pyrazolyl, thienyl, and furanyl. In one preferred embodiment ofthe invention the pyridyl radical is substituted by hydroxy in orthoposition to the nitrogen atom and hence exists at least partially in theform of the corresponding tautomer which is pyridin-(1H)2-one. Inanother preferred embodiment, the pyrimidinyl radical is substituted byhydroxy both in position 2 and 4 and hence exists in several tautomericforms, e.g. as pyrimidine-(1H, 3H)2;4-dione.

Heterocyclyl is especially a five, six or seven-membered heterocyclicsystem with one or two heteroatoms selected from the group comprisingnitrogen, oxygen, and sulfur, which may be unsaturated or wholly orpartly saturated, and is unsubstituted or substituted especially bylower alkyl, such as methyl, phenyl-lower alkyl, such as benzyl, oxo, orheteroaryl, such as 2-piperazinyl; heterocyclyl is especially 2- or3-pyrrolidinyl, 2-oxo-5pyrrolidinyl, piperidinyl,N-benzyl-4-piperidinyl, N-lower alkyl4-piperidinyl, N-loweralkyl-piperazinyl, morpholinyl, e.g. 2- or 3-morpholinyl,2-oxo-1H-azepin-3-yl, 2-tetrahydrofuranyl, or 2-methyl-1,3-dioxolan-2-yl.

Salts are especially the pharmaceutically acceptable salts of compoundsof formula I.

Such salts are formed, for example, as acid addition salts, preferablywith organic or inorganic acids, from compounds of formula I with abasic nitrogen atom, especially the pharmaceutically acceptable salts.Suitable inorganic acids are, for example, halogen acids, such ashydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organicacids are, for example, carboxylic, phosphonic, sulfonic or sulfamicacids, for example acetic acid, propionic acid, octanoic acid, decanoicacid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid,succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid,malic acid, tartaric acid, citric acid, amino acids, such as glutamicacid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleicacid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoicacid, salicylic acid, 4-aminosalicylic acid, phthalic acid, phenylaceticacid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid,2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid,1,5-naphthalene-disulfonic acid, 2-, 3- or 4-methylbenzenesulfonic acid,methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid,N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamicacid, or other organic protonic acids, such as ascorbic acid.

In the presence of negatively charged radicals, such as carboxy orsulfo, salts may also be formed with bases, e.g. metal or ammoniumsalts, such as alkali metal or alkaline earth metal salts, for examplesodium, potassium, magnesium or calcium salts, or ammonium salts withammonia or suitable organic amines, such as tertiary monoamines, forexample triethylamine or tri(2-hydroxyethyl)amine, or heterocyclicbases, for example N-ethyl-piperidine or N,N′-dimethylpiperazine.

When a basic group and an acid group are present in the same molecule, acompound of formula I may also form internal salts.

VEGFR is vascular endothelial growth factor receptor.

FGFR is fibroblast growth factor receptor.

PDGFR is platelet-derived growth factor receptor.

The invention further relates to the use of COMPOUND or a N-Oxide or apharmaceutically acceptable salt thereof for the manufacture ofmedicament having an activity on protein kinases VEGFR-2, Tie-2, c-Src,c-Met, FGFR-1, Fit-1, HER-2, c-Abl, c-Raf, PDGFR-beta, c-Kit, or on acombination of the above enzymes, for the treatment and/or prevention ofneurological and vascular disorders related to beta-amyloid generationand/or aggregation such as neurodegenerative diseases like Alzheimer'sdisease, Down's Syndrome, memory and cognitive impairment, dementia,amyloid neuropathies, brain inflammation, nerve and brain trauma,vascular amyloidosis, or cerebral hemorrhage with amyloidosis.

The invention also relates to a combination of COMPOUND or apharmaceutically acceptable salt thereof with one or more drugs used forthe treatment of neurological and vascular disorders related tobeta-amyloid generation and/or aggregation such as neurodegenerativediseases like Alzheimer's disease, Down's Syndrome, memory and cognitiveimpairment, dementia, amyloid neuropathies, brain inflammation, nerveand brain trauma, vascular amyloidosis, or cerebral hemorrhage withamyloidosis to treat warm-blooded animals including mammals, especiallyhumans.

Depending on species, age, individual condition, mode of administration,and the clinical picture in question, effective doses, for example dailydoses of about 10-1000 mg, preferably 10-50 mg or 50-200 or 200-400,especially 50-100 or 300-400 mg, are administered to warm-bloodedanimals of about 70 kg bodyweight. For adult patients with neurologicaland vascular disorders related to beta-amyloid generation and/oraggregation, especially neurodegenerative diseases like Alzheimer'sdisease, Down's Syndrome, memory and cognitive impairment, dementia,amyloid neuropathies, brain inflammation, nerve and brain trauma,vascular amyloidosis, or cerebral hemorrhage with amyloidosis.

The invention relates likewise to a process or a method for thetreatment of neurological and vascular disorders related to beta-amyloidgeneration and/or aggregation, especially neurodegenerative diseaseslike Alzheimer's disease, Down's Syndrome, memory and cognitiveimpairment, dementia, amyloid neuropathies, brain inflammation, nerveand brain trauma, vascular amyloidosis, or cerebral hemorrhage withamyloidosis. The COMPOUNDS or N-oxides thereof can be administered assuch or especially in the form of pharmaceutical compositions,prophylactically or therapeutically, preferably in an amount effectiveagainst the said diseases, to a warm-blooded animal, for example ahuman, requiring such treatment. In the case of an individual having abodyweight of about 70 kg the daily dose administered is fromapproximately 0.01 g to approximately 5 g, preferably from approximately0.25 g to approximately 1.5 g, more preferably 0.01 g to 0.05 g, evenmore preferably 0.025 g to 0.1 g most preferably 0.05 g to 1 g of acompound of the present invention.

The invention relates also to a method for administering to a humansubject suffering from a neurological and vascular disorders related tobeta-amyloid generation and/or aggregation, especially neurodegenerativediseases like Alzheimer's disease, Down's Syndrome, memory and cognitiveimpairment, dementia, amyloid neuropathies, brain inflammation, nerveand brain trauma, vascular amyloidosis, or cerebral hemorrhage withamyloidosis, COMPOUND or a pharmaceutically acceptable salt thereof,which comprises administering a pharmaceutically effective amount ofCOMPOUND or a pharmaceutically acceptable salt thereof to the humansubject, preferably once daily for a period exceeding 3 months. Theinvention relates especially to such method wherein a daily dose of 200to 800 mg, or 10 mg to 200 mg especially 400-600 mg or 10-100 mg,preferably 400 mg or 10-50 mg, of salt is administered.

The invention also relates in a combination which comprises (a) COMPOUNDor a pharmaceutically acceptable salt thereof and (b) a therapeuticagent for the treatment of neurological and vascular disorders relatedto beta-amyloid generation and/or aggregation, most preferably acombination wherein the combination partners are present insynergistically effective amounts.

The effective dosage of each of the combination partners employed in thecombination may vary depending on a variety of factors including theparticular combination of the pharmaceutical compound partners, theroute of administration, the severity of the disease, the renal andhepatic functions of the patient. The molar ratio (a)/(b) of thecombination partners is about 0.1 to 10, most preferably 0.3 to 3 andthe unit dosage form contains 20 to 200 mg, most preferably 50 to 150 mgof4-Methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamideof the formula I.

EXAMPLE 1

Cell Culture

HEK/APPswe cells are plated in microtiter plates precoated with 10 μg/mlpoly-D-lysine at 12,000 cells/well in 100 μl/well DMEM mediumsupplemented with 10% FCS, 0.25 mg/ml G418 sulfate, 1% penicillinstreptomycin. The following day, supernatant is replaced with 90 μl/wellof fresh medium and 10 μl/well of compound diluted in culture medium areadded. Two types of control wells are used: cell culture medium withoutcells plus 10 μl/well of all compound dilutions (background signals) andcell culture medium from untreated cells (positive control). 24 hourslater after compound addition, conditioned medium is collected and Aβlevels determined by a specific sandwich ELISA.

Aβ₄₀ and Aβ₄₂ Detection by Sandwich ELISA

For the sandwich ELISA, the maxisorp microtiterplates are coatedovernight at 4° C. with 100 μl/well of the monoclonal antibody 25H10diluted 1:1000 in PB for Aβ₄₀ detection or monoclonal antibody B10E7diluted 1:2750 for detection of Aβ₄₂. Wells are then emptied, washedthree times with 350 μl PBS and blocking is performed for 2 hours atroom temperature with 200 μl/well of 2% BSA, 0.05% Tween20 in PBS. Afterwashing the wells as described above, 10 μl of the conditioned mediasamples to be tested are added to wells containing 90 μl of medium and0.18 μg/ml of biotinylated monoclonal β1 antibody and incubatedovernight at 4° C. Wells were washed as described above and 100 μl/wellof alkaline phosphatase coupled to streptavidin diluted 1:5,000 inmedium are added. After 1 hour incubation at room temperature wells arewashed as described above and alkaline phosphatase activity isdetermined by adding 100 μl/well of diethanolamine buffer, pH 9.8 (100mM diethanolamine, 1 mM MgCl₂, pH adjusted to 9.8 with 2 M HCl)containing the chemiluminescent CSPD substrate (25 mM stock solutiondiluted 1:416) and the enhancer Emerald II (diluted 1:10). After 15minutes incubation at room temperature in the dark, plates are measuredon the luminometer (Analyst AD; LJL Biosystems, USA Aβ₄₀). Values aregiven as % reduction of A{tilde over (β)}. The 100% reduction value iscalculated from a series of wells containing only medium and extract andthe 0% reduction value from conditioned medium only. Samples aremeasured in triplicate. A reference compound is included in all platesas control for assay performance.

MTS Assay

To determine cytotoxicity, cells are tested by the MTS colorimetric kitperformed essentially according to the manufacturer's specifications(Promega, #G5430X). After collecting the conditioned medium for thesandwich ELISA, the rest of the conditioned medium is removed completelyand replaced with 100 μl/well culture medium containing one fifth of MTSsolution prepared as recommended in the kit. After 3 hours incubation at37° C., absorbance is read at an OD of 490 nm with a referencewavelength set to 630 nm. Values are given as % metabolic rate (n=6).The 0% value is calculated from wells which had no cells, 100% fromwells with an untreated cell layer

EXAMPLE 24-Methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide

This compound has the following activities in cell-free enzyme assays:VEGFR-2 3.2 microM Tie-2 4.6 microM c-Src 4.6 microM c-Met 4.7 microMFGFR-1 6.7 microM Flt-1 7.7 microM HER-2 7.2 microM c-Abl 295 nM c-Raf-11.1 microM PDGFR-beta 5.8 microM c-Kit 7.8 microM

The compound of example 1 demonstrated a clear reduction of Abetasecretion in the medium of HEK/APPswe cell cultures at concentrationsbelow 10 microM, without having any effect on cellular viability.

1. A method for the treatment and/or prevention of neurological andvascular disorders related to beta-amyloid generation and/or aggregationcomprising administering an inhibitor of one or more protein kinasesVEGFR-2, Tie-2, c-Src, c-Met, FGFR-1, Flt-1, HER-2, c-Abl, c-Raf,PDGFR-beta and c-Kit.
 2. The method according to claim 1 wherein theinhibitor is a compound of formula I

wherein R₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl,acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-loweralkyl, or phenyl-lower alkyl; R₂ represents hydrogen, lower alkyl,optionally substituted by one or more identical or different radicalsR₃, cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono-or bicyclic heteroaryl group comprising zero, one, two or three ringnitrogen atoms and zero or one oxygen atom and zero or one sulfur atom,which groups in each case are unsubstituted or mono- or polysubstituted;and R₃ represents hydroxy, lower alkoxy, acyloxy, carboxy, loweralkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl,amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an arylgroup, or a mono- or bicyclic heteroaryl group comprising zero, one, twoor three ring nitrogen atoms and zero or one oxygen atom and zero or onesulfur atom, which groups in each case are unsubstituted or mono- orpolysubstituted; or wherein R₁ and R₂ together represent alkylene withfour, five or six carbon atoms optionally mono- or disubstituted bylower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy,amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl orpyrimidinyl; benzalkylene with four or five carbon atoms; oxaalkylenewith one oxygen and three or four carbon atoms; or azaalkylene with onenitrogen and three or four carbon atoms wherein nitrogen isunsubstituted or substituted by lower alkyl, phenyl-lower alkyl, loweralkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl,N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, loweralkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl,pyrimidinyl, or pyrazinyl; R₄ represents hydrogen, lower alkyl, orhalogen; or a pharmaceutically acceptable salt thereof.
 3. A methodaccording to claim 1 wherein the inhibitor is a compound selected from,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzanilide,4-Methyl-N-(3-pyridinyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,N-(4-Chlorophenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,2(R)- and2(S)-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoylamino]propanoicacid,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(8-quinolinyl)benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-[trifluoromethoxy]phenyl)benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(2-pyrrolidinoethyl)benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-pyrrolidinophenyl)benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(1-[2-pyrimidinyl]-4-piperidinyl)benzamide,N-(4-Di-[2-methoxyethyl]amino-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,N-(4-[1H-Imidazolyl]-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(2-pyrrolidino-5-trifluoromethylphenyl)benzamide,N-(3,4-difluorophenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifluoromethylbenzyl)benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifluoromethylphenyl)benzamide,N-(3-Chloro-5-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,N-(4-Dimethylaminobutyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,4-Methyl-N-[4-(4-methyl-1-piperazinyl)-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2,2,2-trifluoroethoxy)-3-trifluoromethylphenyl]benzamide,4-Methyl-N-[4-(2-methyl-1H-imidazolyl)-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,4-Methyl-N-(4-phenyl-3-trifluoromethylphenyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,4-Methyl-N-[4-(4-methyl-1H-imidazolyl)-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,Methyl 2(R)- and2(S)-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoylamio]-3-[4-hydroxyphenyl]propanoate,N-[2-(N-Cyclohexyl-N-methylaminomethyl)phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,N-[3-[2-(1H-Imidazolyl)ethoxy]phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,4-Methyl-N-[3-morpholino-5-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(4-pyrrolidino-3-trifluoromethylphenyl)benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(4-piperidino-3-trifluoromethylphenyl)benzamide,4-Methyl-N-[4-morpholino-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,N-(4-Ethylamino-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifluoromethoxyphenyl)benzamide,N-[4-(2-Hydroxypropylamino)-3-trifluoromethylphenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,N-(4-Diethylamino-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(3-pyridinyl)-5-trifluorophenyl]benzamide,N-[3-[3-(1H-Imidazolyl)propoxy]phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino)-N-[4-(3-pyridinyl)-3-trifluorophenyl]benzamide,4-Methyl-N-[3-(4-methyl-1-piperazinyl)-5-trifluorophenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,4-Methyl-N-[3-methylcarbamoyl-5-trifluorophenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide,4-Methyl-N-[3-methylcarbamoyl-5-morpholino]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide.4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[3-(1H-imidazol-1-yl)propoxy]-phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[2-(1H-imidazol-1-yl)ethoxy]phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(ethylamino)-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(diethylamino)-3-(trifluoromethyl)phenyl]benzamide,(±)-4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-[(2-hydroxypropyl)amino]-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-[bis(2-methoxyethyl)amino]-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1-piperidinyl)-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-morpholinyl)-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-phenyl-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[4-(3-pyridinyl)-3-(trifluoromethyl)phenyl]methyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2,4-dimethyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(4-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-morpholinyl)-5-[(methylamino)carbonyl]phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[(methylamino)carbonyl]-5-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(3-pyridinyl)-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-morpholinyl)-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(5-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide,4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl]benzamide,and4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl]benzamide;or a pharmaceutically acceptable salt thereof.
 4. A method according toclaim 1 wherein the inhibitor is4-Methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide;or a pharmaceutically acceptable salt thereof.
 5. A method according toclaim 1 wherein a daily dose of 10 to 800 mg of a compound isadministered to an adult human.
 6. A method according to claim 1 whereinthe disease to be treated is selected from Alzheimer's disease, Down'sSyndrome, memory and cognitive impairment, dementia, amyloidneuropathies, brain inflammation, nerve and brain trauma, vascularamyloidosis, or cerebral hemorrhage with amyloidosis.
 7. A methodaccording to claim 1 wherein the disease to be treated is Alzheimer'sdisease.
 8. A method of treating mammals suffering from neurological andvascular disorders related to beta-amyloid generation and/or aggregationwhich comprises administering to a said mammal in need of such treatmenta pharmaceutical composition comprising (a) a dose, effective againstneurological and vascular disorders related to beta-amyloid generationand/or aggregation, of4-Methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamidehaving the formula I

 or a pharmaceutically acceptable salt thereof and (b) a therapeuticallyeffective amount of a second drug selected from drugs used to treatneurological and vascular disorders related to beta-amyloid generationand/or aggregation.
 9. (canceled)
 10. A pharmaceutical compositioncomprising a compound of formula I

wherein R₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl,acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-loweralkyl, or phenyl-lower alkyl; R₂ represents hydrogen, lower alkyl,optionally substituted by one or more identical or different radicalsR₃, cycloalkyl, benzcycloalkyl, heterocyclyl, an aryl group, or a mono-or bicyclic heteroaryl group comprising zero, one, two or three ringnitrogen atoms and zero or one oxygen atom and zero or one sulfur atom,which groups in each case are unsubstituted or mono- or polysubstituted;and R₃ represents hydroxy, lower alkoxy, acyloxy, carboxy, loweralkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl,amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, an arylgroup, or a mono- or bicyclic heteroaryl group comprising zero, one, twoor three ring nitrogen atoms and zero or one oxygen atom and zero or onesulfur atom, which groups in each case are unsubstituted or mono- orpolysubstituted; or wherein R₁ and R₂ together represent alkylene withfour, five or six carbon atoms optionally mono- or disubstituted bylower alkyl, cycloalkyl, heterocyclyl, phenyl, hydroxy, lower alkoxy,amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl orpyrimidinyl; benzalkylene with four or five carbon atoms; oxaalkylenewith one oxygen and three or four carbon atoms; or azaalkylene with onenitrogen and three or four carbon atoms wherein nitrogen isunsubstituted or substituted by lower alkyl, phenyl-lower alkyl, loweralkoxycarbonyl-lower alkyl, carboxy-lower alkyl, carbamoyl-lower alkyl,N-mono- or N,N-disubstituted carbamoyl-lower alkyl, cycloalkyl, loweralkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl,pyrimidinyl, or pyrazinyl; R₄ represents hydrogen, lower alkyl, orhalogen; or a pharmaceutically acceptable salt thereof for the treatmentof neurological and vascular disorders related to beta-amyloidgeneration and/or aggregation.